Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

Kristina M. Jordahl*, Anna Shcherbina*, Andre E. Kim, Yu Ru Su, Yi Lin, Jun Wang, Conghui Qu, Demetrius Albanes, Volker Arndt, James W. Baurley, Sonja I. Berndt, Stephanie A. Bien, Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Arif Budiarto, Peter T. Campbell, Robert Carreras-Torres, Graham CaseyTjeng Wawan Cenggoro, Andrew T. Chan, David V. Conti, Christopher H. Dampier, Matthew A. Devall, Virginia Díez-Obrero, Niki Dimou, David A. Drew, Jane C. Figueiredo, Steven Gallinger, Graham G. Giles, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Heather Hampel, Sophia Harlid, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Amit D. Joshi, Temitope O. Keku, Susanna C. Larsson, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Bharuno Mahesworo, Victor Moreno, John L. Morrison, Neil Murphy, Hongmei Nan, Rami Nassir, Polly A. Newcomb, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Paul D.P. Pharoah, Elizabeth A. Platz, John D. Potter, Ross L. Prentice, Gad Rennert, Edward Ruiz-Narvaez, Lori C. Sakoda, Peter C. Scacheri, Stephanie L. Schmit, Robert E. Schoen, Martha L. Slattery, Mariana C. Stern, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Natalia Zemlianskaia, Jenny Chang-Claude, W.J. Gauderman, Li Hsu, Anshul Kundaje, Ulrike Peters

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)


BACKGROUND: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. METHODS: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. RESULTS: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. CONCLUSIONS: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.


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